HERV-K (human endogenous retrovirus type K) type 1-encoded Np9 is a tumor-specific biomarker, but its oncogenic role and targets in human leukemia remain elusive. We first identified Np9 as a potent viral oncogene in human leukemia. Silencing of Np9 inhibited the growth of myeloid and lymphoblastic leukemic cells, whereas expression of Np9 significantly promoted the growth of leukemia cells in vitro and in vivo. Np9 not only activated ERK, AKT and Notch1 pathways but also upregulated β-catenin essential for survival of leukemia stem cells. In human leukemia, Np9 protein level in leukemia patients was substantially higher than that in normal donors (56% vs 4.5%). Moreover, Np9 protein level was correlated with the number of leukemia stem/progenitor cells but not detected in normal CD34(+) hematopoietic stem cells. In addition, Np9-positive samples highly expressed leukemia-specific pol-env polyprotein, env and transmembrane proteins as well as viral particles. Thus, the viral oncogene Np9 is a critical molecular switch of multiple signaling pathways regulating the growth of leukemia stem/progenitor cells. These findings open a new perspective to understand the etiology of human common leukemia and provide a novel target for treating leukemia.

Bcr-Abl tyrosine kinase inhibitors (TKIs) have been a remarkable success for the treatment of Ph ؉ chronic myeloid leukemia (CML). However, a significant proportion of patients treated with TKIs develop resistance because of leukemia stem cells (LSCs) and T315I mutant Bcr-Abl. Here we describe the unknown activity of the natural product berbamine that efficiently eradicates LSCs and T315I mutant BcrAbl clones. Unexpectedly, we identify CaMKII ␥ as a specific and critical target of berbamine for its antileukemia activity. Berbamine specifically binds to the ATPbinding pocket of CaMKII ␥, inhibits its phosphorylation and triggers apoptosis of leukemia cells. More importantly, CaMKII ␥ is highly activated in LSCs but not in normal hematopoietic stem cells and coactivates LSC-related ␤-catenin and Stat3 signaling networks. The identification of CaMKII ␥ as a specific target of berbamine and as a critical molecular switch regulating multiple LSC-related signaling pathways can explain the unique antileukemia activity of berbamine. These findings also suggest that berbamine may be the first ATP-competitive inhibitor of CaMKII ␥, and potentially, can serve as a new type of molecular targeted agent through inhibition of the CaMKII ␥ activity for treatment of leukemia. (Blood. 2012; 120(24):4829-4839) IntroductionChronic myeloid leukemia (CML), which accounts for approximately 20% of all adult leukemias, 1 is characterized by the presence of the Philadelphia chromosome (Ph ϩ ), which results from a chromosomal translocation between the Bcr gene on chromosome 22 and the Abl gene on chromosome 9. 2 This translocation produces the fusion protein Bcr-Abl that has constitutive kinase activity 3 and is essential for the growth of CML cells and has become an attractive target for treatment of Ph ϩ CML cases, and the Abl tyrosine kinase inhibitors (TKIs) are now first-line therapeutic agents. [4][5][6] Inhibition of Bcr-Abl with Abl tyrosine kinase inhibitors (TKIs), such as imatinib (IM), is highly effective in controlling CML at chronic phase but not curing the disease. This is largely because of the inability of these kinase inhibitors to kill leukemia stem cells (LSCs) responsible for initiation, drug resistance, and relapse of CML 4-6 and Bcr-Abl gene mutation, particularly T315I mutant Bcr-Abl clones. 7-9 Thus, drug resistance associated with TKIs has created a need for more potent and safer therapies against other targets apart from the Bcr-Abl oncogenic kinase.Increasing evidence shows that traditional Chinese medicine (TCM) products not only play important roles in the discovery and development of drugs, but can also be used as molecular probes for identifying therapeutic targets. Homoharringtonine, arsenic trioxide, and triptolide are 3 famous examples. 9-11 Berbamine (BBM) is a structurally unique bisbenzylisoquinoline isolated from TCM Berberis amurensis, and has been used in traditional Chinese medicine for treating a variety of diseases from inflammation to tumors for many years. 12,13 It possesses a unique profile ...

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